personalized medicine a new challenge for applied human ... - agah€¦ · • expression of adme...

Personalized Medicine A new challenge for applied human pharmacology?

Jochen Theis, MD FFPM InHeCon

Leipzig

2nd March 2012

© InHeCon Jochen Theis 2nd March 2012 2

Personalized Medicine: Predicting Variability in Drug Response

• Genetic polymorphisms of ADME enzymes and transporters

• Expression of ADME enzymes and transporters (reduced/increased)

• Inhibition of ADME enzymes and transporters

• SNPs (B-RAF V600E/vemurafenib)

• Gene Expression (Her2/trastuzumab)

• Immunology (HLA-B*5701/abacavir)

• Viral characteristics (CCR5 tropism/ maraviroc)

• RNA “Footprint” (Oncotype DX/ adjuvant chemotherapy)

Variability in drug exposure Variability in targets and pathways

A Predictive Marker indicates the likelihood of a specific response to a specific therapy:

Pharmacodiagnostic Marker


Personalized Medicine: Past, Present, Future


1950s-1960s: Antibiotic Resistance Testing

M Piquette-Miller and D M Grant: Clinical Pharmacology & Therapeutics 81, 311-315 (March 2007)


1998: Herceptin (trastuzumab)

Clinical Trials Assay (CTA) vs HercepTest® • Her2 is the molecular target for trastuzumab • Standardized immunohistochemistry (IHC) assay developed at Genentech for

phase I-III clinical trials; 2+ or 3+ protein overexpression required for study entry • All testing performed at a central core laboratory (LabCorp) • CTA establishes a de facto standard – but CTA was not commercially viable

=> Requirement for commercially available HER2 test for marketing of Herceptin • Genentech partners with DAKO to develop a commercially available IHC kit

Applications received simultaneous approval by CBER and CDRH on September 25, 1998

From: Cheryl A. Madsen, July 29, 2004

1998: Stratified Therapy: The “Prototype” Herceptin

RRR FISH pos: 43% FISH neg: 0%

ARR FISH pos: 23% FISH neg: 0%

NNT FISH pos: 4 FISH neg: ∞ (all: 20)

⇒ Indication: Pat. with metastatic breast cancer that overexpress HER2

Normal Cell Tumor Cell Tumor Cell +

HER2

• Response rates (Mass R et al. Proc ASCO 2001)

Her2-Amplifizierung

Chemo Chemo + Trastuzumab

FISH negative 38% 38%

FISH positive 31% 54%

Today: Personalized Medicine – Increased Complexity

Normal Cell Tumor Cell Tumor Cell +

HER2

Dako IHC test / other IHC tests / FISH / . . .

Roche/Genetech GSK Herceptin Lapatinib

At launch: Today:

Dako IHC test

Roche/Genetech Herceptin

Tomorrow

?


October 4, 2006: Press Release on PLX4032 Plexxikon Inc. and Roche .. announced …to develop and commercialize PLX4032, (Vemurafenib), which selectively inhibits B-RafV600E, a mutated form of the BRAF kinase gene. The BRAFV600E gene has been associated with increased tumor aggressiveness and decreased survival in … approximately 70% of malignant melanomas … PLX4032 may offer a new treatment modality for the … cancer patients … who carry the BRAFV600E gene. Plexxikon … plans to initiate a Phase 1 clinical trial by the end of this year. Separately, Roche Molecular Diagnostics … and Plexxikon announced they will collaborate on development of an in vitro assay to screen for the presence of the BRAFV600E mutation in biological samples taken from patient tumors.


Safety Study of PLX4032 in Patients With Solid Tumors (Phase 1) Information provided by: Plexxikon ClinicalTrials.gov Identifier: NCT00405587

Primary Outcome Measures: Maximum tolerated dose, Dose-limiting toxicities, Safety Secondary Outcome Measures: Pharmacodynamic activity in tumor biopsy tissue Inclusion Criteria: • Solid tumors confirmed histologically whose tumors are refractory to standard

therapy, or for whom standard or curative therapy does not exist. • Patients from whom paired melanoma biopsies are planned must have a

V600E+ BRAF mutation confirmed prior to the administration of PLX4032 • Patients in the Extension cohorts (melanoma or adenocarcinoma of the colon

or rectum) must have both a V600E+ BRAF mutation • ............

Predictive/Pharmacodiagnostic Markers in Phase I


Predictive BMs in a Typical Clinical Study

Screening visit (selecting the right patients) Last (follow up) visit

Control Visits

Baseline assessment visit

Treatment

First dose visit

Does the patient or disease have a characteristic that predicts a specific response to the drug?


Responders defined by Pharmacodynamic Markers

Screening visit (selecting the right patients) Last (follow up) visit

Control Visits

Baseline assessment visit

Treatment

First dose visit

Does the patient or disease have a characteristic that predicts a specific response to the drug?


Pharmacodynamic Response Markers

Flaherty et al., NEJM 2010


Personalized Medicine: Past, Presence, Future


Future Challenges: Responder Identification

PAROXETINE

• Indication: Major Depression, ...

• Dos.: 20 mg/day, increase in 10mg steps to max 50 mg/day

• “Symptomatic improvement in about 50% of treated patients”

• Relative Risk Reduction (RRR): 19%

• Absolute Risk Reduction (ARR): 11%

• Number needed to treat (NNT): 9 Data from CMAJ. 2008 Jan 29;178(3):296-305. Percentages used from data on improving depression scores

16


Drug Development with a Focus on Personalized / Stratified Medicine

what are the key challenges? how can these challenges best be met? is there a role for applied human pharmacologists?


The Basis for Personalized Medicine: Innovation

Biomarker Technologies “Yesterday” Biomarker Technologies “Today”


Study Conduct & BM Logistics

Biomarker Technologies Drug Development

Clinical Study Design

integrated data management & analysis

New capabilities → New complexities

adaptive designs


Biomarker technologies “yesterday versus today”

Biomarker Technologies “Today”

Biotech

Pharma

Engineering

Academia

Research Institutes

What Biomarkers/Diagnostics do we Need?

Adaptation and Utilisation in

Drug Development

Pharma

Technology Innovation – HARNESSED by Pharma


1. Target Selection

2. Clinical Lead Selection

3. Clinical Candidate Selection

BM discovery: Requirements: single BM point of contact (senior BM expert) to pull in overall BM expertise, medical biology/technology background, able to challenge; funds required

BM qualification: Support to assist with CCS; test development; IVD development (possibly first Dx contact); facilitate the linking of BM data with biological activity for optimal decision making

Confirmatory BM phase: BM needs for early decision making should be understood, ideally integration into GLP tox, integration into clinical plan & clinical protocols

4. Entry in Human

Utilisation of BMs: Dose finding; HV or pat. heterogenicity;

storage strategy; etc.

Biomarkers in Early R&D Projects – when?


PhII PhIII FDA approval,

launch PhI

Drug - Diagnostic Test Co-Development The Regulatory Perspective

Pre-clin

Target selection

Identification of stratification

Clinical utility for stratification

Clinical validation

Label considerations based on marker status

Label considerations based on trial

Marker assay validation

Analytical validation of Diagnostic kit

Clinical validation of Diagnostic kit; final platform

Adapted from FDA Drug-Diagnostic Co-Development Concept Paper

Target validation

Discovery Research C l i n i c a l

Platform change


PhII PhIII FDA approval,

launch PhI

Drug - Diagnostic Test Co-Development Late scenario (end of Ph II or later)

Pre-clin

Target selection

Identification of markers for stratification

Clinical validation

Label considerations based on marker identification

Label considerations based on trial

Target validation

Discovery Research C l i n i c a l

Diagnostics development and platform change at risk

Best case outcomes after late start: • Pharma development at full speed – no co-launch • Allow time of diagnostic development after phase III – late launch • Allow time for platform development prior to phase III – pharmacodiagnostic delay • Very high risk of delays in any case – nightmare for commercial (pricing etc.)


Enabling Personalized/Stratified Medicine

• Biomarker “discovery” – early identification of BMs, understanding the related science (ideally at target selection!) – assessment of utility in human experimentation

• Biomarker “development” (Fit for Purpose !) – BM characterisation & validation (technical, biological, clinical) – design of BM kit suitable for clinical studies (multicentre !)

• Clinical trial design and conduct – selection of suitable population (healthy subjects/challenge?, patients?, which patients?) – obtaining suitable phenotypic data for responder / non-responder identification – acceptance of biomarkers by investigators and patients – BM logistics – BM data management and statistics – agreed decision making criteria (supporting go/no go decision?)

• Clinical utility of pharmacodiagnostic markers – ensuring that pharmacodiagnostic markers do not become bottleneck or controlling – commercial aspects on market size and accessibility

• Timing – Completion of all required activities prior to clinical study start, to decision making, to launch


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